COOH-terminal fragment of APP interacts with p62, forms an aggregate, and induces autophagic degradation in Alzheimer's cell model.
COOH-terminal fragment of APP interacts with p62, forms an aggregate, and induces autophagic degradation in Alzheimer's cell model.
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APP 的 COOH 末端片段与 p62 相互作用，形成聚集体，并在阿尔茨海默病细胞模型中诱导自噬降解。
DOI：
10.1152/ajpcell.00003.2022
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Hosoi T.
中科院分区：
文献类型：
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作者：
Tanaka K;Kuramoto K;Nakagawa T;Nomura Y;Ozawa K;Hosoi T.
阿尔茨海默病是一种难治性疾病，β淀粉样蛋白在大脑中的积累被认为与疾病的发病有关。此外，由于自噬缺陷引起的异常蛋白质积累也可能参与疾病进展。自噬涉及一种称为选择性自噬的机制。然而，选择性自噬和淀粉样前体蛋白（APP）之间的关系仍不清楚。在本研究中，我们分析了衔接蛋白p62和APP相关分子之间的相互作用，发现p62与APP的COOH末端片段（C60）相互作用。当C60和p62过表达时，形成聚集体，C60通过自噬降解。即使使用还原剂，这些聚集体也不容易降解。我们还发现，自噬体和溶酶体标记阳性囊泡中形成的C60和p62表达细胞。超分辨技术还显示，在细胞中形成p62-C60阳性的自噬体。总之，这些结果表明，p62可能与C60结合形成聚集体并诱导自噬体中的自噬。这些结果揭示了阿尔茨海默病进展的潜在机制之一，其中可能涉及选择性自噬。
Alzheimer’s disease is an intractable disease, and the accumulation of amyloid β in the brain is thought to be involved in the onset of the disease. Additionally, abnormal protein accumulation due to autophagic deficiency may also be involved in disease progression. Autophagy involves a mechanism called selective autophagy. However, the relationship between selective autophagy and the amyloid precursor protein (APP) remains unclear. In the present study, we analyzed the interaction between p62, an adapter protein, and an APP-related molecule and found that p62 interacted with the COOH-terminal fragment of APP (C60). When C60 and p62 are overexpressed, aggregates are formed and C60 is degraded by autophagy. These aggregates cannot be easily degraded, even with a reducing agent. We also found that autophagosome- and lysosome marker-positive vesicles were formed in the C60- and p62-expressing cells. Superresolution technology also revealed that p62-C60-positive autophagosomes were formed in the cells. Overall, these results suggest that p62 may bind with C60 to form aggregates and induce autophagy in autophagosomes. These results reveal one of the mechanisms underlying the progression of Alzheimer’s disease, in which selective autophagy may be involved.